Cancer, and cancer treatment, cause many symptoms that can adversely affect quality of life. Despite the development of improved symptom management interventions, and several evidence- and consensus-based guidelines, their timely delivery remains uneven in the health care system. Our research center, Northwestern University IMPACT (NU IMPACT), builds upon an integrated cancer symptom monitoring and management system (NMPRO), currently deployed by our health care delivery system. We will test the effectiveness of a system-wide symptom management intervention when implemented across the Northwestern Memorial HealthCare Corporation (NMHC) outpatient oncology clinics. Using a clinic-level randomized roll-out implementation trial design, we will further test, using an embedded patient-level randomized controlled clinical trial, the effectiveness of an enhanced care (EC) approach aimed to engage participants actively, and to increase self-efficacy, in the monitoring and managing of their symptoms. The existing NMPRO will constitute usual care (UC), and added patient engagement and activation features will comprise the EC condition. This innovative hybrid trial design allows for a within- and between-site evaluation of implementation along with a sufficiently powered group-based comparison to demonstrate effectiveness on individual patient outcomes. We propose three specific aims that target both patient- and system-level outcomes. Aim 1: Implement a fully-integrated oncology symptom assessment and management program across six clinical units that are part of the NMHC healthcare delivery system; Aim 2: Evaluate the impact of the program by conducting a hybrid Type I effectiveness-implementation trial to evaluate the enhanced care program (EC: symptom monitoring & self-management intervention), relative to usual care (UC) on patient- and system-level outcomes; Aim 3: Identify facilitators and barriers to implementation and disseminate to other health systems. We will enroll an estimated 12,671 participants. To address possible contamination effects within each clinical unit, and allow for unit-level data collection for pre- and post-implementation comparison within and across clinical units, 50% will be enrolled and followed prior to program implementation. The other half will be enrolled post-implementation and will be randomly assigned at a 1:1 ratio (stratified by sex and cancer phase; curative intent, non-curative intent & survivorship) to UC versus EC. Fatigue, pain, anxiety, and depression will be assessed using PROMIS computerized adaptive tests (CATs). In addition, we will assess patient clinical outcomes, including healthcare utilization, and cancer treatment delivery outcomes. The NU IMPACT study design allows joint evaluation of system-level implementation and patient-level effectiveness metrics. An extensive array of longitudinal EHR data will be integrated using custom informatics tools and deployed for statistical analysis using plans that blend psychometric and biostatistical outcome evaluation models. Successful elements of this intervention approach will then be extended to widespread adoption.